This project integrates ongoing P50-supported research progress in the Ransohoff lab, and related work from the lab of our collaborator Claudia Lucchinetti, now serving as co-PI. The P50 competing renewal represents a substantial extension of work ongoing in the Pis' labs. The emphasis is on cortical demyelination and meningeal inflammation early in MS, as well as leukocyte trafficking to the cortex and subarachnoid space. P50 research will be leveraged through Dr. Lucchinetti's R01NS49577, on which Dr. Ransohoff is co-PI. During analysis of biopsy material from early MS cases in the Lucchinetti lab, cortical demyelination (CDM) proved to be a common finding and collaboration with the Ransohoff group disclosed frequent association with meningeal inflammation. Notably, biopsies were performed to examine white matter changes on MRI, and the findings of CDM with meningeal inflammation were unexpected. These findings however correlate well with MRI reports demonstrating diffuse and focal cortical damage in early MS. Taken in the context of other recent results, our data in early MS suggest the novel hypothesis that meningeal inflammation and CDM promote white matter lesions during the MS disease process. This hypothesis will be addressed in Specific Aims 1 and 2 and will include detailed phenotyping of leukocytes within CDM lesions, including analysis of chemokine receptors. Importantly, recent studies in animal models identified specific chemokine receptors as candidate trafficking determinants for meninges and cortex. In Aim 3, we will use a novel flow-based in-vitro blood-brain barrier (BBB) model to define which chemokine receptors are essential for transmigration, enabling the identification of potential therapeutic targets for selective suppression of meningeal inflammation and cortical demyelization, and to refine our interpretation of research results obtained during performance of Aims 1 and 2.